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Blood, 15 February 2008, Vol. 111, No. 4, pp. 2073-2082.
Prepublished online as a Blood First Edition Paper on November 20, 2007; DOI 10.1182/blood-2007-06-097576.
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IMMUNOBIOLOGY
In vivo transformation of mouse conventional CD8 + dendritic cells leads to progressive multisystem histiocytosis
Quynh-Giao Steiner1,
Luc A. Otten1,
M. John Hicks2,
Gürkan Kaya3,
Frederic Grosjean1,
Estelle Saeuberli1,
Christine Lavanchy1,
Friedrich Beermann4,
Kenneth L. McClain5, and
Hans Acha-Orbea1
1 Department of Biochemistry, Faculty of Biology and Medicine, University of Lausanne, Epalinges, Switzerland;
2 Department of Pathology, Baylor College of Medicine, Houston, TX;
3 Department of Dermatology, University of Geneva, Geneva, Switzerland;
4 Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Ecole Polytechnique Féderale de Lausanne, Epalinges sur Lausanne, Switzerland; and
5 Baylor College of Medicine, Texas Children's Cancer Center/Hematology Service, Houston, TX
Division and proliferation of dendritic cells (DCs) have been proposed to contribute to homeostasis and to prolonged antigen presentation. Whether abnormal proliferation of dendritic cells causes Langerhans cell histiocytosis (LCH) is a highly debated topic. Transgenic expression of simian virus 40 (SV40) T antigens in mature DCs allowed their transformation in vivo while maintaining their phenotype, function, and maturation capacity. The transformed cells were differentiated splenic CD8 alpha–positive conventional dendritic cells with increased Langerin expression. Their selective transformation was correlated with higher steady-state cycling compared with CD8 alpha–negative DCs in wild-type and transgenic mice. Mice developed a DC disease involving the spleen, liver, bone marrow, thymus, and mesenteric lymph node. Surprisingly, lesions displayed key immunohistologic features of Langerhans cell histiocytosis, including expression of Langerin and absence of the abnormal mitoses observed in Langerhans cell sarcomas. Our results demonstrate that a transgenic mouse model with striking similarities to aggressive forms of multisystem histiocytosis, such as the Letterer-Siwe syndrome, can be obtained by transformation of conventional DCs. These findings suggest that conventional DCs may cause some human multisystem LCH. They can reveal shared molecular pathways for human histiocytosis between humans and mice.
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